KR20010043418A - Aqueous process for manufacturing paroxeting solid dispersions - Google Patents

Abstract

A process for preparing solid, amorphous paroxetine comprising: (A) mixing paroxetine free base or a pharmaceutically acceptable paroxetine salt with water and pharmaceutically acceptable polymer; and (B) drying to form a composition comprising amorphous paroxetine and polymer, eliminating the need for organic solvents common for the solvent process. The resultant amorphous solid paroxetine composition is free from crystalline form, and yet has good handling properties, making it suitable for pharmaceutical use in the traditional tablet dosage form.

Description

Aqueous process for the preparation of paroxetine solid dispersions {AQUEOUS PROCESS FOR MANUFACTURING PAROXETING SOLID DISPERSIONS}

Compound (-)-trans-4-((4'-fluorophenyl) 3- (3'4'-methylenedioxyphenoxymethyl) -piperidine ((-)-trans-4, also known as paroxetine) -((4'-fluorophenyl) 3- (3'4'-methylenedioxyphenoxymethyl) -piperidine) is a viscous oil and a low water-soluble drug that is widely used as a pharmaceutical composition, especially for depression.

US Pat. No. 4,721,723 describes crystalline paroxetine hydrochloride hemihydrate as a novel material having better operating properties than enhydros paroxetine hydrochloride, an absorbent solid with low operating properties.

International patent application WO 96/24595 describes paroxetine hydrochloride sorbate in addition to propan-2-ol sorbate as a precursor in the preparation of paroxetine hydrochloride with little binding organic solvent. WO 96/24595 also describes four novel paroxetine hydrochloride enhydrates with few binding organic solvents.

International patent application WO 97/03670 discloses (1) swelling in water in the presence of an active agent selected from the group comprising SSRI's such as paroxetine, but (a) at least about 80% has at least one carboxyl functionality. Containing about 0.05-1.5% polyalkenyl polyether-free crosslinking agent based on the weight of each of the plurality of repeating units and (b) the unpolymerized repeating unit and the crosslinking agent, and are insoluble and fibrous A controlled release paroxetine formulation comprising a calcium polycarbophil component, which is a crosslinked carboxy-functional polymer of and (2) a reaction complex formed by interaction with water, is described.

A more particular aspect of the WO 97/03670 application is (a) a deposit-core comprising an active material having an effective amount of determined geometry and (b) a support-platform attached to the deposition-nucleus above. A system for controlled release of an active ingredient that is an SSRI such as paroxetine, wherein the deposition-nucleus is at least the active substance and (1) a polymerizable gelable polymer with a polymeric member that swells upon contact with water or an aqueous liquid Material and (2) at least one member selected from the group comprising a single polymeric material having both swelling and gelling properties, the support platform being attached to the deposition-nucleus as an elastic support and partially depositing the nucleus. It can cover the surface of, slowly dissolve and / or gel slowly in aqueous solution.

Therefore, there has been a need in the art for novel methods for introducing paroxetine, a low water soluble drug, into solid dispersions and their use in pharmaceutical compositions containing the same.

Summary of the Invention

The invention is one side,

(A) mixing paroxetine free base or pharmaceutically acceptable paroxetine salt with water and a pharmaceutically acceptable polymer; And

(B) a method for producing a solid, amorphous paroxetine comprising the step of drying to form a composition comprising amorphous paroxetine and a polymer.

In another aspect, the invention encompasses pharmaceutical compositions and polymers of the paroxetine salts in amorphous, solid form prepared by the methods described above.

In another aspect, the invention is a method of treating a warm blooded animal comprising administering a therapeutically effective amount of a pharmaceutical composition prepared according to the invention.

The aqueous solvent process of the present invention provides an amorphous solid form that has distinct advantages over the crystalline forms of the prior art and eliminates the need for organic solvents.

The present invention relates to methods of preparing pharmaceutical compositions, resulting compositions and their use. In particular, the present invention relates to pharmaceutical formulations of paroxetine, methods of making such formulations, pharmaceutical compositions containing the formulations, and their use in the treatment.

Paroxetine is the generic name for the compound described in Example 2 of US Pat. No. 4,007,196 and also refers to (-)-trans-4-((4'-fluorophenyl) 3- (3'4'-methylenedioxyphenoxy Methyl) -piperidine and pharmaceutically acceptable salts thereof Paroxetine freebase is a viscous oil at standard temperature and pressure Paroxetine salt is an acid addition product of paroxetine, for example hydrochloric acid addition product It is called "paroxetine hydrochloride" or "paroxetine hydrochloride salt".

The paroxetine compounds described herein have two asymmetric centers. Unless stated otherwise, the (-)-trans isomer is preferably an enantiomer. However, all chiral, diastereomeric and racemic types are all available. It is known in the art how to produce optically active forms, such as by separation of racemic forms from optically active starting materials or by synthesis. It is intended that all chiral, diastereomeric or racemic forms be used unless a particular stereochemistry or isomeric form is specifically indicated.

Pharmaceutically acceptable polymeric carriers used in the present invention include, for example, hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose , Polyvinyl alcohol, polypropylene, dextran, dextrins, hydroxypropyl-beta-cyclodextrin, chitosan, co (lactic / glycolide) copolymer, poly (orthoester), poly (enhydrate), polyvinyl Chloride, polyvinyl acetate, ethylenevinyl acetate, lectins, carbopols, silicone elastomers, polyacrylic polymers, maltodextrin, lactose, fructose, inositol, trehalose, maltose, raffinose, polyvinylpyrroli Don (PVP), Polyethylene Glycol (PEG), Alpha-, Beta-, Persimmon Ma-cyclodextrin or a suitable mixture thereof.

Preferred polymeric carriers are one or more polyvinylpyrrolidones, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol, wherein more preferred polymer carriers are about 2,500 Polyvinylpyrrolidone (PVP) with an average molecular weight of about 3,000,000. Most preferred polymer carriers are polyvinylpyrrolidone having an average molecular weight of about 10,000 to about 450,000. Since immediate release formulations are known to be the most desirable, it is preferred that the polymer is not a property that modulates or delays the release of paroxetine from the solid tablet formulation.

Pharmaceutically acceptable carriers are capable of kneading both paroxetine free bases and salts, and maintaining the salts in a uniform amorphous solid state dispersion after the water has been removed by distillation, free bases of the active ingredient, salts of free bases It is preferable that it is chemically inert with respect to a water-soluble acid solution. The polymer is preferably at least partially meltable and even more preferably completely water soluble.

Suitable salts that are pharmaceutically acceptable include, but are not limited to, minerals or organic acid salts, quaternary ammonium salts, and the like. Examples of pharmaceutically acceptable salts include those derived from inorganic acids such as hydrochloride, bromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; And acetic acid, propionic acid, succinic acid, glycolic acid, stearic acid, lactic acid, malic acid, tathalic acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, gutamic acid, benzoic acid, salicylic acid, sulfanic acid, Salts prepared from organic acids such as 2-acetoxybenzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, ethanedisulfonic acid, oxalic acid, isetionic acid and the like.

Pharmaceutically acceptable salts of paroxetine can be prepared by the delivery or introduction of part of the acid by a variety of methods. Some of the acids can be introduced in a compact form or in aqueous solution. Salts are generally prepared by reacting the free base with an excess or stoichiometric amount of the desired salt-forming inorganic or organic acid.

A list of suitable salts is described, for example, in Remington's Pharmaceutical Sciences, 17th Edition, Mack Publishing, Easton, PA 1985, p. Found in 1418

Paroxetine may be added in free base or in salt form. When paroxetine is added in the form of a free base, the method includes adding an acid corresponding to a pharmaceutically acceptable base of paroxetine to the mixture or a solution of the free base. The free base is converted into the salt in that state, for example by the addition of an inorganic or organic acid. The acid can be added in the form of a solid dissolved in gas, liquid or water. Preferred acids are hydrochlorides and the molar amount of acid added to the solution of the paroxetine free base and the carrier can be added in an stoichiometric proportion to the paroxetine free base or in particular when added in gas.

The preferred range of hydrochloride added is from about 1.0 to about 1.8 times the molar amount of paroxetine freebase. The preferred molar ratio of paroxetine to hydrochloride is 1: 1 to 1: 1.8 and more preferably 1: 1.1. Although hydrochloride is easily added as a gas, a preferred method of adding hydrochloride is to add the hydrochloride in dissolved form in water. It is understood that the salt of the free base produced upon addition of the acid remains dissolved in solution with the polymer carrier.

Paroxetine, polymer carriers, and water can be mixed in any order. These are preferably mixed in one way to form a solution of the paroxetine salt and the polymer.

If the temperature does not result in the decomposition or degradation of any substance, heating the solution is not essential at low concentrations in forming a solution of the polymer carrier and water. It is very desirable at high concentrations. It is preferred to add the paroxetine free base or paroxetine salt after dissolving the polymer in water suitably between 25 ° C. and 100 ° C., preferably between 45 ° C. and 80 ° C. When paroxetine is added to the free base, the final solution preferably forms a salt at a clean temperature. In the most preferred embodiment, for different concentrations and implementations, the result is a clean solution of paroxetine salt formed at a temperature of at least about 60 ° C., although a clean solution is produced at different temperatures. It is only good to heat enough to form a clean solution.

The weight ratio of pharmaceutically acceptable water soluble polymer carrier to paroxetine is in the range of 20: 1 to 0.5: 1, preferably 4: 1 to 1: 1, more preferably 3: 1 to 1.5: 1 , Most preferably 2: 1.

It is preferable that a clean solution is formed. When forming the desired clean solution, the process proceeds by recovering water to form a solid dispersion of the free base salt in the polymer carrier. Although evaporation or spray drying under vacuum is desired, any method of water removal is possible which results in a uniform solid state dispersion. Preferred drying methods under vacuum include rotovaporation, static vacuum drying or a combination thereof. One skilled in the pharmaceutical formulations can determine the appropriate temperature at which water can be removed under conditions where the temperature is too high to cause decomposition or degradation of the material. However, evaporation is preferably from 25 ° C to 100 ° C. It is also desirable for the evaporation of water to be uniform and consequently to a solid state without water. As a result, the absence of water means that the solid dispersion contains up to 20% by weight of residual moisture, preferably up to 10%, more preferably up to 5% and most preferably up to 1%.

In addition to the amorphous paroxetine salt, other active ingredients may be added to form more combinations than one drug which is preferably amorphous in water-soluble form. Since calcium polycarbophil has conventionally been used as a release controlling agent, a solid formulation without calcium polycarbophil is highly preferred in view of the immediate release formulation. Indeed, compositions without any water swellable, insoluble, fibrous crosslinked carboxy-functional polymers are preferred and they have been used for controlled release in the past.

The ratio of paroxetine to pharmaceutically acceptable polymer carrier can vary over a wide range and depends on the concentration of paroxetine required in the finally administered pharmaceutical dosage form.

The ratio of paroxetine free base to pharmaceutically acceptable polymer carrier can vary over a wide range and depends on the concentration of paroxetine required in the finally administered pharmaceutical dosage form. However, the preferred range of paroxetine in the solid dispersion is from about 16% to 50% of the total solid dispersion weight, more preferably from 20% to 50%, even more preferably from 25% to 40%, most preferably Is 33% of the total dispersion weight. The preferred range in terms of weight ratio of polymer to paroxetine is 0.4: 1 to 20: 1.

Appropriate pharmaceutically acceptable excipients may be added to the method. Suitable pharmaceutical excipients are known from the Pharmaceutical Sciences of Remington, Mack Press, which is a standard reference in this field.

Examples of pharmaceutically acceptable excipients include diluents, binders, disintegrants, colorants, fragrances, lubricants and / or preservatives.

The pharmaceutical composition may be formed by conventional mixing methods such as kneading, tableting, granulating, compacting. Such agents can be used in conventional manner, for example, in a manner similar to those already clinically used in anti-depressants.

The composition is usually expressed in unit dosage compositions containing 1 to 200 mg, more generally 5 to 100 mg, for example 10 to 50 mg, such as 12.5, 20, 25 or 30 mg. Such compositions are usually taken from 1 to 6 times daily, for example 2, 3 or 4 times daily, so that the total amount of active agent administered is 5 to 400 mg.

Preferred unit dosage forms include tablets or capsules.

The invention also provides a method of treating depression in a mammal, including a human, which method comprises the administration of a therapeutically effective amount of a pharmaceutically acceptable solid state dispersion of paroxetine hydrochloride.

The invention further provides a formulation of paroxetine hydrochloride for use in treating depression.

Administration can be by any method of inhibiting serotonin re-uptake in the mammalian body, making contact of the active agent to the active region of the agent. Administration can be used for use in combination with a pharmaceutical agent or in combination with a therapeutic agent by any common method.

Of course, the dosage may include the pharmacodynamic properties of the particular agent and their mode and route of administration; Age, health, weight of the prisoner; The nature and extent of the symptoms; The kind of concurrent treatment; Number of treatments; It will vary depending on known factors such as the desired effect.

Dosage forms (compositions suitable for administration) contain from about 0.1 mg to about 100 mg of active ingredient per unit. In such pharmaceutical compositions the active ingredient is usually present in an amount of about 0.5-50% by weight of the composition.

The active ingredient can be added orally in solid dosage forms such as capsules, tablets and powders.

Gelatin capsules contain active ingredients and excipients such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid and the like. Similar excipients can be used to make compressed tablets. Tablets and capsules can be prepared as sustained release products that provide sustained release of the drug over several hours. Compressed tablets may be coated with a film or sugar to mask any unpleasant taste or to protect the tablet from the atmosphere or enteric coated for selective degradation in the esophagus.

Some examples of pharmaceutical dosage forms for the administration of the compounds of the invention are illustrated as follows.

Unit capsules may be prepared by filling a solid standard two-piece gelatin with 10 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate, respectively.

Mixtures of the active ingredients can be prepared in edible oils such as soybean oil, cottonseed oil or olive oil and injected into the gelatin using a positive replacement pump to form soft gelatin capsules containing 10 mg of the active ingredient.

Tablets may be prepared by conventional procedures, eg, in dosage units of 10 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, 98.8 mg of lactose. have. Appropriate coatings may be applied to delay absorption or enhance palatability.

The following examples further illustrate and exemplify the specific implementation of the invention, but do not limit it. Examples 1-5 illustrate the preparation of solid state dispersions and 6, 7 illustrate pharmaceutical compositions.

Example 1 PVP 29/32 K / paroxetine hydrochloride, 2: 1 Wt based, oven dried

A 125 mL Erlenmeyer flask was charged with PVP 29/32 K (8.1210 g), paroxetine free base (4.62 g) and purified hot water (60 ° C., 48 mL). The Erlenmeyer flask was placed in a water bath heated to 60 ° C. Hot 1.0 N HCL (13.6 mL at 60 ° C.) was added to a 125 mL Erlenmeyer flask and stirred for about 5 minutes. Approximately 5 mL of hot solution was transferred to a pre-heated crystallization dish (60 ° C.) using a pipette and dried in a tray oven at 60 ° C. for 71 hours. The solid product, named EN320-135A, was tested using FTIR (FIG. 1) and X-ray powder diffraction (FIG. 2). The results of FTIR analysis were consistent with PVP and paroxetine hydrochloride as a whole. No crystal peaks were found in the X-ray powder diffraction, indicating that there was no paroxetine crystal and that paroxetine was only in an amorphous state. FTIR data were collected using a Nicolet 510 P FT-IR spectrometer. Nujol mulls were prepared for the samples and analyzed in KBr plates. X-ray powder pattern was obtained using Bruker Analytical GADDS system. The diffractometer was equipped with a point x-ray source and a two-dimensional area detector. The emission was CuK (alpha, 50 kV, 40 mA). Data were collected from 2 to 60 degrees (the degree) 2-theta at room temperature; The sensor range was 30 degrees; The number of frames was three; Data recruitment time was 600 sec / frame. Samples were loaded by inserting the sample into a small round sample mount for reflection mode data recruitment.

¹ H NMR analysis (CDCL ₃ ) was consistent with the mixture of PVP and paroxetine hydrochloride as a whole, and to specific signals for PVP (series of br 3.8-1.6) and paroxetine hydrochloride (2.9, br.dt). Showed expected resonance for the

Basic Analysis: 8.121: 5.13 (by weight) Calcd. For PVP and Paroxetine HCL .:% C, 62.33; % H, 7.34; % N, 8.72; % Cl, 3.62; % F, 1.94.

Found:% C, 60.72; % H, 7.28; % N, 8.67; % Cl, 3.87; % F, 2.07.

Example 2 PVP 29/32 K / paroxetine hydrochloride, 2: 1 Wt based, vacuum drying

About 5 mL of the hot solution prepared in Example 1 was placed in a preheated round bottom flask (60 ° C.) using a pipette. The sample was dried at 60 ° C. for 29 hours under static vacuum. The solid product, named EN320-135B, was tested using FTIR (FIG. 3) and X-ray powder diffraction (FIG. 4). The results of FTIR analysis were consistent with PVP and paroxetine hydrochlorad. X-ray powder diffraction indicated no crystal peaks, no paroxetine crystals, and paroxetine only present in an amorphous state. FTIR data were collected using a Nicolet 510 P FT-IR spectrometer. Nujol mulls were prepared for the samples and analyzed in KBr plates. X-ray powder pattern was obtained using Bruker Analytical GADDS system. The diffractometer was equipped with a point x-ray source and a two-dimensional area detector. The emission was CuK (alpha, 50 kV, 40 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The sensor range was 30 degrees; The number of frames was three; Data recruitment time was 600 sec / frame. Samples were loaded by inserting the sample into a small round sampler for reflection mode data recruitment.

¹ H NMR analysis (CDCL ₃ ) was consistent with the mixture of PVP and paroxetine hydrochloride as a whole, and to specific signals for PVP (series of br 3.8-1.6) and paroxetine hydrochloride (2.9, br.dt). Showed expected resonance.

Basic Analysis: 8.121: 5.13 (by weight) Calcd. For PVP and Paroxetine HCL .:% C, 62.33; % H, 7.34; % N, 8.72; % Cl, 3.62; % F, 1.94.

Found:% C, 61.49; % H, 7.30; % N, 8.84; % Cl, 3.89; % F, 2.03.

Example 3 PVP 29/32 K / paroxetine hydrochloride, 2: 1 Wt basis, fluid bed drying

In a 250 mL flask (equipped with a magnetic stirrer), polyvinylpyrrolidone (PVP), paroxetine hydrochloride enhydroisopropyl alcohol solution (7.0058 g), having a molecular weight distribution of 29/32 K (14.0097 g) Purified water (85.366 g) was filled. The contents of the flask were heated to a temperature of approximately 60 ° C. using a hotplate stirrer to obtain a stirred and clear solution. The hot solution was spray dried on dibasic calcium phosphate dihydrate (100 g) using a bench-top fluid bed dryer. FTIR (FIG. 5) analysis of a solid named EN320-006, a glass-flow powder, was consistent with a mixture of dibasic calcium phosphate dihydrate, PVP and paroxetine hydrochloride. X-ray powder diffraction (FIG. 6) analysis of the powder indicated overall agreement with the mixture of dibasic calcium phosphate and PVP, no paroxetine crystals and the presence of only paroxetine in an amorphous state. FTIR data were collected using a Nicolet 510 P FT-IR spectrometer. Nujol mulls were prepared for the samples and analyzed in KBr plates. X-ray powder patterns were obtained using a Philips Model 3720 automated powder diffractometer. The diffractometer was equipped with theta-compensating slit, scintillation counter and graphite monochromator. The emission was CuK (alpha, 40 kV, 30 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The size of the step was 0.02 degrees; Counting time was 0.5 sec / step. Samples were made from thin films of powdered material in a dry knit state in a glass sample mount.

Example 4 PVP 29/32 K / paroxetine hydrochloride, 1: 1 Wt basis, fluid bed drying

A 250 mL flask (equipped with a magnetic stirrer) was charged with PVP 29/32 K (22.24 g), paroxetine hydrochloride enhydro isopropyl alcohol sorbate (22.21 g) and purified water (278 g). The contents of the flask were heated to a temperature of approximately 60 ° C. using a hotplate stirrer to obtain a stirred and clear solution. The hot solution was spray dried onto dibasic calcium phosphate dihydrate (187.344 g) using a bench-top fluid bed drier. FTIR (FIG. 7) analysis of a solid named EN320-073, a glass-flow powder, was consistent with a mixture of dibasic calcium phosphate dihydrate, PVP and paroxetine hydrochloride. X-ray powder diffraction (FIG. 8) analysis of the powder indicated overall agreement with the mixture of dibasic calcium phosphate and PVP, no paroxetine crystals and the presence of paroxetine in only an amorphous state. FTIR data were collected using a Nicolet 510 P FT-IR spectrometer. Nujol mulls were prepared for the samples and analyzed in KBr plates. X-ray powder pattern was obtained using Bruker Analytical GADDS system. The diffractometer was equipped with a point x-ray source and a two-dimensional area detector. The emission was CuK (alpha, 50 kV, 40 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The sensor range was 30 degrees; The number of frames was three; Data recruitment time was 600 sec / frame. Samples were loaded by inserting the sample into a small round sampler for reflection mode data recruitment.

Example 5 PVP 29/32 K / Paloxetine Hydrochloride, 0.5: 1 Wt Based, Fluidized Bed Drying

A 250 mL flask (equipped with a magnetic stirrer) was charged with PVP 29/32 K (11/11 g), paroxetine hydrochloride enhydro isopropyl alcohol sorbate (22.21 g) and purified water (279.1 g). The contents of the flask were heated to a temperature of approximately 60 ° C. using a hotplate stirrer to obtain a stirred and clear solution. The hot solution was spray dried with dibasic calcium phosphate dihydrate (100.0 g) using a bench-top fluid bed drier. FTIR (FIG. 9) analysis of a solid named EN320-104, a glass-flow powder, was consistent with a mixture of dibasic calcium phosphate dihydrate, PVP and paroxetine hydrochloride. X-ray powder diffraction (FIG. 10) analysis of the powder indicated overall agreement with the mixture of dibasic calcium phosphate and PVP, with no paroxetine crystals and the presence of paroxetine in only an amorphous state. FTIR data were collected using a Nicolet 510 P FT-IR spectrometer. Nujol mulls were prepared for the samples and analyzed in KBr plates. X-ray powder pattern was obtained using Bruker Analytical GADDS system. The diffractometer was equipped with a point x-ray source and a two-dimensional area detector. The emission was CuK (alpha, 50 kV, 40 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The sensor range was 30 degrees; The number of frames was three; Data recruitment time was 600 sec / frame. Samples were loaded by inserting the sample into a small round sampler for reflection mode data recruitment.

Example 6 A 21 mg paroxetine HCl tablet

A 21 mg tablet was prepared according to Example 3, using a solid dispersion, named EN 320-006 and having the following ingredients and amounts.

ingredient mg / tablet gm / ash Paroxetine HCL 21.00 3.51 PVP 29 / 32K * 42.00 7.02 Dibasic Calcium Phosphate Dihydrate * 300.11 50.17 Sodium starch glycolate 24.00 4.00 Magnesium stearate 9.00 1.50 gun 396.11 66.2

* Theoretical quantities of paroxetine HCl, PVP and dibasic calcium phosphate dihydrate

Tablets were made according to the following procedure: Milling paroxetine HCl / PVP / dibasic calcium phosphate dihydrate by passing through a 20 mesh screen. The milled material is mixed with sodium starch glycolate, magnesium stearate. Compress the tablets to a weight of 396.11 mg. Tablets are coated with a commercially used color film coating. X-ray powder diffraction (FIG. 11) analysis was performed on base tablets (Lotte EN320-006) with the coating removed after 14 weeks storage at 40 ° C./75% relative humidity. The diffractogram was generally consistent with the dibasic calcium phosphate dihydrate, PVP, a mixture of sodium starch glycolate and magnesium stearate, indicating that there was no paroxetine crystals and paroxetine was only in an amorphous state. X-ray powder patterns were obtained using a Philips Model 3720 automated powder diffractometer. The diffractometer was equipped with theta-compensating slits, scintillation counters and graphite monochromators. The emission was CuK (alpha, 40 kV, 30 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The size of the step was 0.02 degrees; Counting time was 0.5 sec / step. Samples were made from thin films of powdered material in a dry knit state in a glass sample mount.

Example 7 A 22.21 mg paroxetine HCl purification using the solid dispersion described in Example 4

A 22.21 mg paroxetine HCl tablet was prepared using the solid dispersion of Example 4 (EN320-073).

ingredient mg / tablet gm / ash Paroxetine HCL 22.21 20.11 PVP 29 / 32K * 22.24 20.14 Dibasic Calcium Phosphate Dihydrate * 187.44 169.75 Dibasic Calcium Phosphate Dihydrate 29.15 26.40 Sodium starch glycolate 24.00 21.74 Magnesium stearate 15.00 13.59 gun 300.00 271.73

* Theoretical quantities for paroxetine HCl, PVP and dibasic calcium phosphate dihydrate products are described in Example 4.

Tablets were made according to the following procedure: Milling paroxetine HCl / PVP / dibasic calcium phosphate dihydrate by passing through a 20 mesh screen. The milled material is mixed with sodium starch glycolate, magnesium stearate. The tablet is compressed to a weight of 300 mg. Tablets are coated with a commercially used color film coating. X-ray powder diffraction (FIG. 12) analysis was performed on the basic tablet (Lotte EN320-006) with the coating removed after 3 weeks storage at 40 ° C./75% relative humidity. The diffractograms were in overall agreement with dibasic calcium phosphate dihydrate, PVP, a mixture of sodium starch glycolate and magnesium stearate, indicating that there was no paroxetine crystals and paroxetine was only in an amorphous state. X-ray powder patterns were obtained using a Philips Model 3720 automated powder diffractometer. The diffractometer was equipped with theta-compensating slits, scintillation counters and graphite monochromators. The emission was CuK (alpha, 40 kV, 30 mA). Data was collected from 2 to 60 degrees 2-theta at room temperature; The size of the step was 0.02 degrees; Counting time was 0.5 sec / step. Samples were prepared as thin films of powdery material in a dry knit state in a glass sample mount.

While the invention has been described in great detail, various modifications, selective implementations, and improvements to the inventions disclosed herein will be readily apparent to those skilled in the art without departing from the spirit and scope of the invention.

Claims (34)

(A) mixing paroxetine free base or pharmaceutically acceptable paroxetine salt with water and a pharmaceutically acceptable polymer; And (B) A process for preparing a solid, amorphous paroxetine, comprising drying to form a composition comprising a polymer and amorphous paroxetine. The method of claim 1, wherein the polymer is at least partially water soluble. The method of claim 1 wherein said polymer is water soluble. The method of claim 1, further comprising forming a solution of the paroxetine salt and the polymer. The method of claim 1 wherein the polymer is water soluble and the aqueous solution of paroxetine or paroxetine salt is formed during or after the mixing. The method of claim 1 wherein the solid amorphous paroxetine and polymer solid are released immediately. The method of claim 1, wherein the polymer does not have the property of controlling or delaying the release of paroxetine from a solid tablet formulation. The method of claim 1 wherein the solid amorphous paroxetine is a solid amorphous paroxetine swellable in water and free of insoluble, fibrous crosslinked carboxy-functional polymers. The method of claim 1, wherein the paroxetine is added as a pharmaceutically acceptable salt. The method of claim 9 wherein the acid corresponding to the pharmaceutically acceptable salt of paroxetine is a hydrochloride salt. The method of claim 1, wherein the paroxetine is added in free base form, further comprising adding an acid corresponding to the pharmaceutically acceptable salt of paroxetine. The method of claim 11, wherein the molar ratio of paroxetine to the acid is about 1: 1 to 1: 1.8. The method of claim 12, wherein the molar ratio of paroxetine to the acid is from about 1: 1 to about 1: 1.1. The method of claim 11, wherein the paroxetine free base is obtained by basifying the paroxetate salt. The method of claim 11, wherein the acid is HCl, and the molar ratio of paroxetine to HCl is from about 1: 1 to about 1: 1.8, and the polymer is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose. And a block copolymer of ethylene oxide and propylene oxide, polyethylene glycol, wherein the drying step comprises spray drying to form a solid that is mixed with excipients to be tableted. The method of claim 1 wherein said mixing is performed at an elevated temperature. The method of claim 16, wherein the elevated temperature is between about 25 ° C. and 100 ° C. 18. 18. The method of claim 17, wherein the elevated temperature is about 60 ° C. The method of claim 1, wherein the polymer is selected from the group consisting of polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, and polyethylene glycol. 20. The method of claim 19, wherein the polymer is polyvinylpyrrolidone. The method of claim 20, wherein the polyvinylpyrrolidone has an average molecular weight of about 2,500 to about 3,000,000. The method of claim 1 wherein said drying step comprises spray drying on a substrate. The method of claim 22, wherein the substrate is calcium phosphate. The method of claim 1, wherein the resulting dried amorphous solid is mixed and tableted with a pharmaceutically acceptable excipient. The method of claim 24, wherein the pharmaceutically acceptable excipients are calcium carbonate, calcium phosphate, calcium sulfate, cellulose, cellulose derivatives, croscarmellose sodium, cospovidone, dexrate, dextrin, dextrose, fructose, guar Gum, lactose, maltodextrin, mannitol, povidone, starch, sorbitol, sucrose, xylitol. The method of claim 1 wherein the weight ratio of polymer to paroxetine is about 0.4: 1 to 20: 1. A pharmaceutical composition comprising an amorphous paroxetine salt prepared by the method according to claim 1 and a polymer. The method of claim 27, wherein the salt is a hydrochloride, the polymer is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl cellulose, block copolymers of ethylene oxide and propylene oxide, polyethylene glycol A pharmaceutical composition selected from the group consisting of. A method of treating a warm blooded animal comprising administering to said warm blooded animal a therapeutically effective amount of a composition according to claim 27. The method of claim 1, wherein the pharmaceutically acceptable polymer is water soluble. The method of claim 1, wherein the method further comprises forming a clean solution. 32. The method of claim 31, wherein said drying step comprises spray drying said clean solution on a pharmaceutically acceptable excipient to form a solid comprising amorphous paroxetine and a crystalline material. 32. The method of claim 31, wherein said mixing step is performed at an elevated temperature, said polymer is polyvinylpyrrolidone, and said drying step comprises spray drying said clean solution onto an amorphous or crystalline substrate, with the result Dried amorphous paroxetine is mixed with excipients and purified. The method of claim 1, wherein the solid amorphous paroxetine does not have calcium polycarbophil.